Preterm Birth (PTB), commonly defined as delivery of an infant before 37 weeks of gestation, affects 12.6% of all births in the U.S. A major obstacle in preventing and treating PTB has been our incomplete understanding of its etiology and biological mechanisms. Both the literature and our work have provided compelling evidence that PTB is influenced by environmental and genetic factors and their interactions. To date, PTB research has largely omitted epigenomics, which unites mechanisms of nuclear reprogramming during development with environmentally induced biological changes, and the ability of cells to respond to external stimuli. The central focus of this proposal is to identify epigenomic alterations in the context of individual genetic susceptibility and environmental exposures and to gain important insight into the biological mechanisms by which genomic, epigenomic, and environmental factors affect the risk of PTB. We propose to accomplish the following aims. Aim 1: We will conduct epigenomic mapping among 500 African American mothers, including 250 spontaneous very preterm cases and 250 term, normal birth weight controls drawn from the existent Boston Birth Cohort. We will use the Illumina HumanMethylation27 DNA Analysis BeadChip for epigenomic mapping. We will test the hypothesis that alterations of DNA methylation in maternal venous blood samples obtained at birth are associated with the risk of PTB. Aim 2: We will conduct epigenomic mapping among 500 infants born to the mothers included in Aim 1, using the same Illumina platform. We will test the hypothesis that alterations of DNA methylation in cord blood samples obtained at birth are associated with the risk of PTB. Exploratory Analysis: We will utilize the extensive database of the Boston Birth Cohort to simultaneously evaluate the roles of environment, genomic, and epigenomic factors as well as their interactions in PTB. We will also explore the interplay of maternal and fetal epigenome in relation to PTB. This will be the first epigenomic study of PTB in conjunction with GWAS in African American mother-infant pairs, a population with high prevalence of socio-environmental adversities and high risk of PTB. This proposal has many unique features, including a highly cost-efficient study by using an existent well-designed and well-phenotyped birth cohort;an innovative approach to integrate environment, genomic and epigenomic factors in PTB;and a highly interactive and experienced multidisciplinary research team with a track record of collaboration and productivity. This proposed study has a great potential to transform our understanding of the etiology and biological mechanisms of PTB, especially, among high risk inner-city minority populations, which will be of key importance for lowering the incidence of PTB and reducing preterm disparity in the U.S. PUBLIC HEALTH RELEVANCE: In the U.S, more than one out of every eight live births is premature infants (PTB) each year. PTB is a major cause of infant morbidity and mortality and is associated with increased risk for a wide range of short- and long-term health and developmental problems. The central focus of this proposal is to identify maternal and fetal epigenomic alterations in relation to PTB. Findings from this study will help gain important insight into how genomic, epigenomic, and environmental factors affect the risk of PTB.